[unreadable] This application proposes ancillary studies to the NIDDK-Biliary Atresia Research Consortium (BARC). Biliary atresia is a multifactorial disease of variable phenotypes that results from a fibro-inflammatory obstruction of the extrahepatic biliary system in children. Despite the multifactorial nature of disease, we combined patient-based functional genomics and mechanistic studies in experimental biliary atresia to discover a central role for proinflammatory immunity in disease pathogenesis. In preliminary studies, we also applied functional genomics to uncover molecular signatures that are highly distinctive of the two main clinical forms of biliary atresia. Based on these studies, we propose patient-based ancillary studies approved by BARC in which we use stored liver tissue, clinico-histological features at presentation, and prospective data on long-term outcome to define the molecular basis for clinical phenotypes and the determinants of the variable clinical outcomes of children biliary atresia. For these experiments, our overall hypothesis is that integrative genomics yields new molecular phenotypes and predicts long-term outcome in biliary atresia. This hypothesis will be tested by the following specific aims: 1) to determine the transcriptional basis of known clinical forms and discover novel molecular subtypes of biliary atresia, 2) to define molecular signatures that predict outcome of biliary atresia, and 3) to discover transcriptional predictors of favorable response to anti-inflammatory treatment. To achieve these aims, we will create a single data-mining platform that contains key elements of clinical and histological data combined with genome-wide levels of gene expression using livers of infants with biliary atresia at the time of diagnosis and at later phases of disease enrolled in the BARC prospective database study and corticosteroid clinical trial. We will then use state-of-the-art bioinformatics methods to analyze the platform to determine the molecular basis of phenotypic expression and of progression of disease, and to identify biomarkers that predict response to anti-inflammatory treatment. Collectively, the proposed experiments will create unprecedented opportunities to refine the diagnosis of biliary atresia, increase understanding of the biological processes regulating disease progression, and individualize treatment according to molecular biomarkers predictive of response. [unreadable] [unreadable] [unreadable]